1. Field of the Invention
The present invention relates to therapeutic compositions for the repair of connective tissue in humans and animals and, in particular to nutraceutical compositions capable of promoting chondroprotection, the repair and replacement of human and animal connective tissue.
2. Background
The connective tissues of humans and animals are constantly subjected to stresses and strains from mechanical forces that can result in afflictions, such as arthritis, joint inflammation and stiffness. Such afflictions are especially acute in joints, such as the neck, back, arms, hips, ankles and feet. Indeed, connective tissue afflictions are quite common, presently affecting millions of Americans. Further, such afflictions can be both painful and, in their extreme, debilitating.
The treatment of connective tissue afflictions can be quite problematic. A simple decrease in the stress to which the connective tissue is subjected is often not usually an option, especially in the case of athletes and animals such as race horses. Thus, an interruption in the traumatic pathways can often not be achieved. Consequently, especially in the case of human athletes and animals, treatment is often directed at controlling the symptoms of the afflictions and not their causes, regardless of the stage of the degenerative process.
Presently, steroids, such as corticosteroids, and other anti-inflammatory materials, such an NSAIDS or high doses of aspirin, are widely used for the treatment of connective tissue ailments. [Vidal et al., Pharmocol. Res. Commun., 10:557-569 (1978)]. In addition, hyaluronic acid and polysulfated glycosaminoglycan are used in veterinary medicine, especially for equines. Drugs may inhibit the body""s own natural healing processes, leading to further deterioration of the connective tissue.
Connective tissues are naturally equipped to repair themselves by manufacturing and remodeling prodigious amounts of collagen (a chief component of connective tissues) and proteoglycans (PGs)xe2x80x94the other major component of connective tissues. This ongoing process is placed under stress when an injury occurs to connective tissues. In such cases, the production of connective tissue (along with collagen and proteoglycans) can double or triple over normal amounts, thereby increasing the demand for the building blocks of both collagens and proteoglycans.
The building blocks for collagen are amino acids, especially proline, glycine and lysine. Proteoglycans (PGs) are large and complex macromolecules comprised mainly of long chains of modified sugars called glycosaminoglycans (GAGS) or mucopolysaccharides. PGs provide the framework for collagen formation and also hold water to give the connective tissues (especially cartilage) flexibility, resiliency and resistance to compression.
Like almost every biosynthetic pathway in the body, the pathways by which both collagen and GAG form single molecule precursors are quite long. As is also characteristic of other biosynthetic pathways, the pathways by which collagen and GAGs are produced include what is called a rate-limiting stepxe2x80x94that is, one highly regulated control point beyond which there is a commitment to finish. The presence of such rate-limiting steps permits complicated biosynthetic processes to be more easily and efficiently controlled by permitting the organism to focus on one point. For example, if conditions demand production and all the requisite raw materials are in place, then stimulation of the rate-limiting step will cause the end product to be produced. To stop or slow production, the organism needs simply to regulate the rate-limiting step.
In the production of collagen, the rate-limiting step is the maturation, rather than the production, of newly synthesized collagen. Unused collagen in simply degraded back to amino acids. Proteoglycans, however, have a specific rate-limiting step in their production.
In the production of PGs, the rate-limiting step is the conversion of glucose to glucosamine for the production of GAGs. Glucosamine, an aminosugar, is the key precursor to all the various modified sugars found in GAGs, including glucosamine sulfate, galactosamine, N-acetylglucosamine, etc. Glucosamine also makes up to 50% of hyaluronic acidxe2x80x94the backbone of PGsxe2x80x94on which other GAGs, like chondroitin sulfate are added. The GAGs are then used to build PGs and, eventually, connective tissue. Once glucosamine is formed, there is no turning away from the synthesis of GAG polymers and the synthesis of collagen.
Glucosamine has been shown to be rapidly and almost completely absorbed into humans and animals after oral administration. A significant portion of the ingested glucosamine localizes to cartilage and joint tissues, where it remains for long periods. This indicates that oral administration of glucosamine reaches connective tissues, where glucosamine is incorporated into newly-synthesized connective tissue. In vitro, the introduction of glucosamine has been demonstrated to increase the synthesis of collagen and glycosaminoglycans in fibroblasts, which is the first step in repair of connective tissues. In vivo, topical application of glucosamine has enhanced wound healing. Glucosamine has also exhibited reproducible improvement in symptoms and cartilage integrity in humans with osteoarthritis in a series of studies. [L. Bucci, Nutritional Supplement Advisor, (July 1992)].
The pathway for the production of connective tissue may be briefly described as follows. Glucosamine is the main building block of connective tissue and may be provided either through the enzymatic conversion of glucose or through diet or external administration (see FIG. 1). Glucosamine may be converted into the other main component of connective tissue, namely proteoglycans (PGs), upon incorporation of glucosamine into glycosaminoglycans (GAGs) (see FIG. 2).
More specifically, GAGs are large complexes of polysaccharide chains associated with a small amount of protein. These compounds have the ability to bind large amounts of water, thereby producing a gel-like matrix that forms the body""s ground substance. GAGs stabilize and support cellular and fibrous components of tissue while maintaining the water and salt balance of the body. The combination of insoluble protein and the ground substance forms connective tissue. For example, cartilage is rich in ground substance while tendon is composed primarily of fibers.
GAGs are long chains composed of repeating disaccharide units of monosaccharides (aminosugar-acidic sugar repeating units). The aminosugar is typically glucosamine or galactosamine. The aminosugar may also be sulfated. The acidic sugar may be D-glucaronic acid or L-iduronic acid. GAGs, with the exception of hyaluronic acid, are covalently bound to a protein, forming proteoglycan monomers. These PGs consist of a core protein to which linear carbohydrate chains formed of monosaccharides are attached. In cartilage proteoglycan, the species of GAGs include chondroitin sulfate and keratin sulfate. The proteoglycan monomers then associate with a molecule of hyaluronic acid to form PG aggregates. The association of the core protein to hyaluronic acid is stabilized by link proteins.
The polysaccharide chains are elongated by the sequential addition of acidic sugars and aminosugars, and the addition is catalyzed by a family of transferases. Aminosugars, such as glucosamine, are synthesized through a series of enzymatic reactions that convert glucose to glucosamine, or alternatively may be provided through the diet. The glucosamine is then incorporated into the GAGs as described above. Acidic sugars may be provided through the diet, may be obtained through degradation of GAGs by degradative enzymes, or produced through the uronic acid pathway.
Since repeating disaccharide units contain one aminosugar (such as glucosamine), it is clear that the presence of an aminosugar in the production of connective tissue is important. Glucosamine is, by far, the more important ingredient in the production of connective tissue since it is the essential building block of GAGs. See FIG. 1. The glucosamine is provided from the composition of the present invention. All GAGs contain hexosamine or uronic acid derivative products of the glucose pathway and from exogenous glucosamine for example:
Chondroitin sulfate is a GAG that provides a further substrate for the synthesis of the proteoglycans. The provision of the chondroitin in its salt (sulfate) form facilitates its delivery and uptake by the humans and animals in the production of connective tissue. In addition, the sulfate portion of chondroitin sulfate is available for use in catalyzing the conversion of glucosamine to GAGs. Fragments of GAGs, including chondroitin sulfate, may also be used to provide a substrate for synthesis of proteoglycans since the assembly of PG occurs in the extracellular space.
In addition, chondroitin sulfate has been shown to have cardiovascular health benefits. [Morrison et al., Coronary Heart Disease and the Mucopolysaccharides (Glycosaminoglycans), pp. 109-127 (1973)]. Thus, the preferred form of glycosaminoglycan included in the compositions of the present invention is chondroitin sulfate or fragments thereof.
Chondroitin may be more efficacious than glucosamine for injury rehabilitation. [Christensen, Chiropractic Products, pp. 100-102 (April 1993)]. An evaluation of glucosamine versus chondroitin for treatment of osteoarthritis has been conducted and concludes, contrary to Christensen, that glucosamine is preferred. [Murray, MPI""s Dynamic Chiropractic, pp. 8-10 (Sep. 12, 1993)]. Neither reference teaches or suggests combining of the materials. Bucci (Townsend Letter for Doctors, pp. 52-54, January 1994), who was aware of the applicant""s composition and acknowledges personal communication from the applicant, discloses the combination of glucosamine and chondroitin for treatment of osteoarthritis.
Chondroitin sulfate also acts to inhibit the degradative enzymes that break down connective tissue. In so doing, chondroitin sulfate promotes the maintenance of healthy connective tissues. When combined with glucosamine, which functions primarily as a building block for the synthesis of connective tissue, chondroitin sulfate works in concert with the glucosamine but works in a primarily different fashion. The ability of chondroitin sulfate to block degradation is an important function, and chondroitin sulfate is provided in the compositions of the present invention primarily for that reason.
Manganese, a stimulant to the composition, plays a role in the synthesis of GAGs, collagen and glycoproteins which are important constituents of cartilage and bone. For that reason, manganese is an optional ingredient in the compositions of the present invention. Manganese is important for enzyme activity of glycosyltransferases. This family of enzymes is responsible for linking sugars together into glycosaminoglycans, adding sugars to other glycoproteins, adding sulfate to aminosugars, converting sugars into other modified sugars, and adding sugars to lipids. The enzymatic functions of glycosyltransferases are important in glycosaminoglycan synthesis (hyaluronic acid, chondroitin sulfate, keratan sulfate, heparin sulfate and dermatin sulfate, etc.), collagen synthesis, and in the functions of many other glycoproteins and glycolipids. Glycosaminoglycans and collagen are the chief structural elements of all connective tissues. Their synthesis is essential for proper maintenance and repair of connective tissues.
Manganese deficiency leads to abnormal bone growth, swollen and enlarged joints, and slipped tendons in humans and animals. In humans, manganese deficiencies are also associated with bone loss and arthritis. Levels of all glycosaminoglycans are decreased in connective tissues during manganese deficiencies, with chondroitin sulfates being most depleted. Manganese-deficient organisms quickly normalize glycosaminoglycans and collagen synthesis when manganese is replenished.
Manganese is also important for activity of manganese superoxide dismutase (MnSOD), which is present only in mitochondria. Manganese deficiency decreases the activity of MnSOD and may lead to mitochondrial dysfunction, manifested as decreased cellular functions.
Approximately 40% of dietary manganese is absorbed by the body tissue. Storage of manganese in the body is minimalxe2x80x94a mere 12 to 20 mg is present in the body at any one time. Large amounts of calcium and phosphorus in the intestine are known to interfere with absorption. The richest dietary sources are the foods least consumed by the general public as whole grain cereals and breads, dried peas, beans and nuts. The ascorbate form of manganese is preferred in the present invention due to the high bioavailability and the need for vitamin C (ascorbic acid) for collagen production. Vitamin C also enhances manganese uptake by the body. However, other soluble forms of manganese may be used in the present invention as well.
Manganese also plays a role in the synthesis of glycosaminoglycans and glycoproteins, which are important constituents of cartilage and bone. Many reproductive problems in horses and skeletal abnormalities in foals have been ascribed to manganese deficiency. [Current Therapy in Equine Medicine, 2:402-403 (1987)].
3. Description of Prior Art
There are several disclosures of which we are aware wherein it has been suggested to provide exogenous quantities of glucosamine in order to bypass the rate-limiting step of the conversion of glucose to glucosamine in those pathways that produce proteoglycans. For example, the intravenous administration of glucosamine (a precursor of the GAGs) and derivatives thereof have been disclosed in U.S. Pat. No. 3,232,836, issued to Carlozzi et al., for assisting in the healing of wounds on the surface of the body. In U.S. Pat. No. 3,682,076, issued to Rovati, the use of glucosamine and salts thereof is disclosed for the treatment of arthritic conditions. Finally, the use of glucosamine salts has also been disclosed for the treatment of inflammatory diseases of the gastrointestinal tract in U.S. Pat. No. 4,006,224 issued to Prudden.
There have also been several disclosures of which we are aware wherein it has been suggested to go one step further in bypassing the glucose-to-glucosamine rate-limiting step, by providing exogenous quantities of various of the modified sugars found in the GAGs for producing proteoglycans. For example, in U.S. Pat. No. 3,6797,652 issued to Rovati et al., the use of N-acetylglucosamine is disclosed for treating degenerative afflictions of the joints.
In still other disclosures of which we are aware, it has been taught to go still one step further in bypassing the glucose-to-glucosamine rate-limiting step by providing exogenous quantities of the GAGs themselves (with and without various of the modified sugars). For example, in U.S. Pat. No. 3,371,012 issued to Furuhashi, a preservative is disclosed for eye graft material that includes galactose, N-acetylglucosamine (a modified sugar found in the GAGs) and chondroitin sulfate (a GAG). Additionally, U.S. Pat. No. 4,486,416 issued to Soll et al., discloses a method of protecting corneal endothelial cells exposed to the trauma of intraocular lens implantation surgery by administering a prophylactically effective amount of chondroitin sulfate. Also, U.S. Pat. No. 5,141,928 issued to Goldman discloses the prevention and treatment of eye injuries using glycosaminoglycan polysulfates.
U.S. Pat. No. 4,983,580 issued to Gibson, discloses methods for enhancing healing of corneal incisions. These methods include the application of a corneal motor composition of fibronectin, chondroitin sulfate and collagen to the incision.
Finally, in U.S. Pat. No. 4,801,619 issued to Lindblad, the intraarticular administration of hyaluronic acid is disclosed for the treatment of progressive cartilage degeneration caused by proteoglycan degradation.
While the above references have, to varying degrees, been useful for their intended purposes, none has proven entirely satisfactory. In particular, the absorption rates and ability to increase GAG production of the various compositions disclosed in these references have not been entirely satisfactory. In addition, none of the compositions are provided with both the aminosugar starting material in conjunction with a GAG (such as chondroitin sulfate) or fragments of GAGs, including chondroitin sulfate.
Accordingly, it can be seen that there remains a need for a therapeutic composition which includes an aminosugar and GAGs or fragments of GAGs for aiding in the conversion of the building blocks of connective tissue to proteoglycans for facilitating the repair of connective tissue in humans and animals.
It is an object of the present invention to provide a therapeutic composition for the protection and repair of connective tissue in humans and animals.
It is a further object of the present invention to provide such a therapeutic composition which is a nutraceuticalxe2x80x94that is, a composition which includes only naturally-occurring components capable of providing beneficial therapeutic effects.
It is yet another object of the present invention to provide such a nutraceutical which contains an aminosugar and which further contains glycosaminoglycans for facilitating the repair of connective tissue in humans and animals.
It is still a further object of the present invention to provide such a nutraceutical which contains an aminosugar and which further contains fragments of glycosaminoglycans for facilitating the repair of connective tissue in humans and animals.
It is a further object of the present invention to provide such a nutraceutical composition which exhibits increased absorption rates.
In accordance with the present invention, disclosed herein is a composition capable of treating and repairing connective tissue in humans and animals. The composition includes therapeutic quantities of an aminosugar selected from the group consisting of glucosamine, glucosamine salts and mixtures thereof, in combination with a glycosaminoglycan selected from the group consisting of chondroitin, chondroitin salts and mixtures thereof, and fragments of a glycosaminoglycan selected from the group consisting of fragments of chondroitin, fragments chondroitin salts and mixtures of such fragments.
In further accordance with the teachings of the present invention, disclosed herein is a method for the treatment and repair of connective tissue in humans and animals. This method includes administering a therapeutically effective quantity of a therapeutic composition including an aminosugar selected from the group consisting of glucosamine, glucosamine salts and mixtures thereof, in combination with a glycosaminoglycan selected from the group consisting of chondroitin, chondroitin salts and mixtures thereof, and fragments of a glycosaminoglycan selected from the group consisting of fragments of chondroitin, fragments of chondroitin salts and mixtures of such fragments.
These and other objects of the present invention will become readily apparent from a reading of the following description, when taken in conjunction with the enclosed drawing.